The immune response to transplanted tissue is a complex event involving a wide range of inducer and effector mechanisms. Recent studies have suggested that the murine T cell helper/inducer subset characterized by cell surface expression of the CD4 molecule is necessary in the initiation of islet allograft transplantation rejection. Understanding the mechanisms of anti-CD4 mediated unresponsiveness is one of the major aims of this grant application. Data presented below support the central hypothesis to be examined that T cell anergy is induced in recent thymic migrants following depletive anti-CD4 treatment and organ allograft transplantation. A second question will address the potential use of anti-CD4 immunotherapy in islet transplantation as a treatment for autoimmune insulin dependent diabetes mellitus (IDDM). The autoimmune nature of IDDM may preclude the use of anti-CD4 therapy for islet transplants because of the underlying "autoimmune" mechanisms which could destroy transplanted islet tissue despite effective transplantation tolerance strategies for "alloimmunity". Only by determining if anti-CD4 mediated transplantation tolerance is effective in genetically predisposed animal models of IDDM will it be possible to decide whether anti-CD4 mediated islet transplantation tolerance induction provides a potentially successful therapeutic strategy for the treatment of human IDDM. The last aim is to attempt to identify the protein product(s) whose synthesis is required for the induction of anergy. These studies have significance for potential insight into human transplantation tolerance induction regimens and for understanding mechanisms of anti-CD4 induced unresponsiveness. More importantly, they may provide insight into the potential use of anti-CD4 immunotherapy to allow islet transplantation as a treatment of human type I diabetes.